diarrhea - walter reed army institute of research trop. med...• watery diarrhea • low-grade...

Diarrhea

UNCLASSIFIED

Paige E. Waterman, MD Antimicrobial Resistance Pillar Chief

AFHSC-GEIS

Deputy Infectious Diseases Consultant to TSG

SEP 2014

UNCLASSIFIED Slide 2

Outline • Introduction

• Military Disease Burden

• Causative Agents

• Clinical Presentations

• Diagnosis

• Treatment "The death list from disease was a fearful one in the Department of the Gulf. Fever and diarrhea, the former disabling and the latter killing, were worse foes than bullets, ten to one.” – Civil War Union Major and Surgeon S.C. Gordon


Definitions

• Diarrhea: Alteration in normal bowel movements; increase in water content, volume, or frequency of stools.

• Acute diarrhea: < 14 days in duration

• Persistent diarrhea: ≥ 14 days in duration

• Chronic diarrhea: ≥ 30 days in duration


Normal GI Physiology and Regulation

Impact factors


Differential Diagnosis of Diarrhea

Mandell. PPID. 8th Ed. Ch 15.

This lecture.


Differential Diagnosis of Diarrhea


Definitions • Traveler’s diarrhea: Diarrhea developing while traveling

and within 10 days of returning home.

• Classic: 3 or more unformed stools within 24 hours and one of the following: nausea, vomiting, abdominal pain, cramps, fever, blood in stools

• Moderate: 1 or 2 unformed stools in 24 hours plus one of the above symptoms –or- more than 2 stools in 24 hours without symptoms

• Mild: passage of 1 or 2 unformed stools within 24 hours and no symptoms

• Infectious diarrhea: Diarrhea with an infectious etiology


Impact of Diarrheal Diseases in Modern Military Campaigns

• World War II: ‘A few months of the year, malaria would cause more man-days lost, but on the calendar-year average, gastrointestinal infections were well ahead.’1

• Vietnam War: Diarrhea/dysentery largest single disease threat, leading to 4 times more hospitalizations than malaria.2

• OIF: Acute enteric illness was leading cause of hospital admission among British forces during first 12 months of operations in Iraq.3

(1) Ward TG: History of Preventive Medicine, US Army Forces in the Middle East, 19Oct41 - 23Jun44, Vol. 111. [Official record.] (2) Wells RF, GI Diseases: Background and Buildup. In: Internal Medicine in Vietnam Vol II: General Medicine and ID, US Army

Medical Dept 0:345-354. (3) Grange, C: J Royal Army Medical Corps, 2005:151(2):101-104.

Slide courtesy of CAPT S. Savarino


Force Health Impacts

Afghanistan Vomiting only

Iraq Severe diarrhea Dysentery Diarrhea with fever

13-14% 5-15%

21-27%

2-8% 9-25%

clinical presentations

Missed patrol IV fluids Hospitalized Confined to bedrest Job performance

9-13% 12%

15-17%

13% 45%

2%

Grounded Fecal incontinence

Back-fill needed 6-12%

32%

operational impact



I expect that our imaginations cannot fathom the problems attendant from the absolute urgency for relief from explosive vomiting and diarrhea when experienced within an armored vehicle under fire and at ambient temperature of > 40°C.

David O. Matson, MD

Infectious Diseases Section, Center for Pediatric Research, Norfolk, Virginia

Clinical Infectious Diseases 2005



OEF/OIF, 2001-2007 Disease Burden ‘By the Numbers’

2,134,578 145,871

3,857,002 11,478,270

850,444 17,356

1,114,208 162,279

Cases of diarrhea Diarrhea days Ambulatory Medical Visits Hospitalizations Duty days lost Liters of IV fluids infused

No. deployments (x, 19 d)

No. deployments (x, 183 d)

Cumulative deployments and disease burden



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20

30

40

50

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Diarrhea Respiratory Non-combat injury

Incidence of Illness based on Self-Reporting vs. DNBI

Slide courtesy of C

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avarino


Deployment versus Traveler’s Diarrhea • Q: Are deployed military personnel similar to travelers?

– A: Some ways yes, some ways no.

• YES: Physically relocated. Variation in food and water source. Variation in environmental exposures.

• NO: Stress. Poor sleep hygiene. Food and water not on economy.* Variations in physical activity.

*Exceptions to this rule understood.


Risk Factors for Deployment or Traveler’s Diarrhea

• Geographic location (hygiene standards)

• Number of viable organisms reaching the intestine – Eating habits (wash, peel, cook)

• History of gastric surgery

• Abnormal digestive motility

• Gastric ulcer, antihistaminic drugs

• Immunosuppression

– Malignancy, HIV, medications, etc.


Geographic Risk of Traveler’s Diarrhea


History and Physical Examination • History

– HPI • Duration of illness, number of stools each day, stool

description (water, blood, pus, mucus), other symptoms such as F, S, C, N, or V, efforts to treat and response

– ROS • Extra-intestinal (rash, headache, neurologic, etc.)

– PMHx / PSHx • Immunosuppression, GI anatomy

– SHx • Travel history • Food and water source for last 9-10 days • Sick contacts • Tobacco and ETOH

– Meds • Antibiotics


History and Physical Examination • Physical Examination

– Vitals • HR, BP, Pulse pressure, Orthostatics, Temperature

– HEENT • Sunken eyes, mucus membranes

– Skin • Rash, turgor, perfusion

– Cardiac • Tachycardia

– Lungs • Respiratory rate, clarity of breath sounds

– Abdomen • Bowel sounds, distention, TTP, rebound, etc.

– Extremities • Perfusion


Clinical Presentations

• Dysentery (1-5%) – Fever – Tenesmus – Mucoid stools – Grossly bloody stools

• Gastroenteritis (≤10%)

– Recurrent vomiting

• Watery diarrhea (80%) – ± Abdominal cramps – ± Nausea – ± Vomiting – ± Fecal urgency – ± Low-grade fever


Pathogens, Epidemiologic Settings, Clinical


Pathogens and Clinical Syndromes


Pathogens: Acute Watery Diarrhea

• Bacteria – Enterotoxigenic Escherichia

coli (ETEC) – Enteroaggregative Escherichia

coli (EAEC) – Vibrio cholerae

• Viruses

• Parasites

• Food poisoning


Pathogens: Acute Bloody Diarrhea

• Bacteria

– Enterohemorrhagic E.coli (EHEC)

– Enteroinvasive E.coli (EIEC)

– Shigella species

– Campylobacter species

– Nontyphoidal Salmonella

– Entamoeba histolytica


Persistent Travelers’ Diarrhea • Travelers’ diarrhea is often self-limited

– Majority of cases resolve after several days

• Persistent illness – Lasting >1 week: 10% of cases – Lasting >1 month: 2% of cases

• Etiological considerations with persistent diarrhea

– EAEC (occasionally, Campylobacter, Salmonella) – Parasitic diarrhea

• Giardia lamblia • Cryptosporidium parvum • Cyclospora cayatanensis


Stressors Amplify Diarrhea Morbidity

25

30

35

40

°C

moderate

not ill

mild

severe

Illness severity

Fluid/Electrolyte Losses

Insensible water loss

10

5

15 DEATH

delirium circulatory collapse

confusion

increasing heart rate dizziness

diminished G tolerance

decreased exercise endurance decline in psychomotor performance

% dehydration

0 normal physiologic function



First described among British Forces during WWII (Stewart. Br Med J 1950; 1(4650):405–9)

Approx. 1 in 12 people develop PI-IBS after infectious diarrhea

Higher risk associated with prolonged illness and invasive pathogens

Onset usually occurs within 6 months after infection

Can persists 5-6 years in 60 - 70% of people Halvorson et al, Am J Gastroenterol. 2006; 101:1894-9.

Post-infectious Irritable Bowel Syndrome


Pathogens – Clinical Syndromes


Types of Escherichia coli (E. coli)

• E. coli consists of a diverse group of bacteria • Pathogenic E. coli strains are categorized into pathotypes • Six pathotypes are associated with diarrhea 1). Enterotoxigenic E.coli (ETEC) 2). Enterohemorrhagic E. coli (EHEC) [Shiga toxin-prod. E. coli (STEC)] 3). Enteroaggregative E. coli (EAEC) 4). Enteroinvasive E. coli (EIEC) 5). Enteropathogenic E. coli (EPEC) 6). Diffusely adherent E. coli (DAEC)


Diarrheagenic Escherichia coli: Pathogenesis

adapted from Kaper JB et al Nat Rev Microbiol 2004

• Fimbrial colonization factors mediate enterocyte adherence

• Elaboration of secretory heat-labile (LT), heat-stable (ST) enterotoxins

ETEC • Enterocyte adherence

and biofilm formation • Elaboration of secretory

enterotoxins and cytotoxins

EAEC • Colonic epithelial cell

invasion • Lysis of phagosome • Cell-to-cell spread via

actin microfilament nucleation

EIEC


Diarrheagenic Escherichia coli: Pathogenesis

adapted from Kaper JB et al Nat Rev Microbiol 2004

• Intimate adherence to small bowel enterocytes

• Attaching and effacing lesion, with cytoskeletal derangement

• Induction of inflammatory response

• Induction of attaching and effacing (AE) lesions in the colonic epithelium

• Elaboration and absorption of Shiga toxin (STx)

• Signal transduction effects

• Cellular projections induced that enwrap bacteria

DAEC EPEC STEC


Enterotoxigenic E. coli (ETEC)

• Watery Diarrhea

• Low-grade fever, nausea, malaise, abdominal cramping, and diarrhea

• Occurs within 1 to 3 days of ingestion • Resolves within 3 to 4 days.

• Leading cause of travelers’ diarrhea. • Virulence due to a heat-labile and heat-stable toxin • Contaminated water or food is responsible for transmission • High infective dose of the bacteria is necessary


Enterohemorrhagic E coli (EHEC) / Shiga Toxin Producing E. Coli (STEC)

• Watery diarrhea bloody stools (few days)

• Abdominal pain (RLQ), cramping, fever absent / low-grade. • As many as 10% develop hemolytic uremic syndrome

(HUS). Case fatality rate of 3% to 5%, common cause of renal failure, neurologic sequelae, hemolytic anemia, and thrombocytopenia.

• Incubation period 2-10 days; symptoms up to 2 weeks.

• Adheres to gut epithelium, produces Shiga toxins, (also called verotoxins), similar or identical to the toxin elaborated by Shigella. Best known EHEC serotype is 0157:H7. Antibiotics may pre-dispose to HUS.


Campylobacter jejuni • Watery to dysenteric diarrhea

• Abdominal pain and cramps, and fever. Nausea, vomiting,

headache, and malaise frequently occur. • Complications may include Guillain-Barre syndrome,

hemolytic uremic syndrome, toxic megacolon, cholecystitis, meningitis, and reactive arthritis.

• Incubation period 1-10 days, disease 2-7 days, may be biphasic illness.

• Animal-to-human transmission is common. Improperly cooked chicken is a major source of illness.


Nontyphoidal Samonella • Watery or dysenteric diarrhea

• Nausea, vomiting, abdominal cramping, fever (50%), RLQ

or peri-umbilical pain, 10% with bacteremia, carrier state. • Reiter syndrome is a long-term sequel, ~2% to 29% of

patients, especially among persons with the HLA-B27.

• Incubation 6-48 hours, >1 week reported, persists 4-7 days • Contaminated foods of both plant and animal origin. Fecal-

oral transmission from infected animals or persons. Poultry are prone to colonization by Salmonella; disease transmission while handling birds, consuming undercooked poultry, and eating inadequately cooked eggs. Handling of pet reptiles is another well known source of infection.


Samonella (typhi and paratyphi) • “Pea soup” diarrhea

• Initially, symptoms are absent, then bacteremia, then high

fever, abdominal pain, “rose spots.” Fever becomes more constant with the development of altered mental status.

• Intestinal perforation and hemorrhage may occur. Multi-organ system involvement is frequently present. Untreated typhoid fever carries a mortality rate of 12% to 30%.

• Incubation 1-2 weeks, Illness lasts about 1 month, relapse • A prolonged, antibiotic-resistant carrier state usually

indicates the presence of the disease in the gallbladder and is an indication for cholecystectomy.


Shigella

• Dysenteric stools, blood, mucus

• Lower abdominal pain and small-volume, dysenteric stools. High fever and rectal burning. Illness 1-7 days, may be biphasic, frank hematochezia in the second phase.

• Potential complications include seizures, meningitis, appendicitis, hemolytic-uremic syndrome, reactive arthritis, and postinfection irritable bowel syndrome.

• The incubation period is usually 12 to 96 hours • Species: S dysenteriae, S flexneri, S boydii, and S sonnei • Person-to-person contact, food, water, and fly transmission


Vibrio cholerae

• Voluminous “rice water” stools

• “Classic” cholera: vomiting, abdominal distension, rapid intravascular volume loss, fever and bacteremia in minority

• Incubation 6 hours - 5 days

• Multiple pathogenic species of Vibrio exist (ex. O1, O139) • Contaminated food and water responsible for most illness • Clinical significance of the organism is due to the virulence

of the various toxins elaborated by different strains.


Clostridia difficile

• Watery diarrhea, may contain blood, mucus

• Cramping and tenderness in the lower abdomen, malaise, mild temperature elevation

• Toxic megacolon with fever, abdominal distention / pain

• Risk factors include comorbidities, advanced age, recent (within 3 months) antibiotics, gastric pH

• All antibiotics may cause, Clindamycin, cephalosporins, fluoroquinolones, penicillins most implicated

• Antibiotic-altered gut flora, colonization by C difficile, inflammatory exotoxins toxin A and toxin B


Yersinia enterocolitica

• Diarrhea, may be frankly bloody

• Abdominal pain and fever, RLQ pain may mimic appendicitis. Symptoms typically persist for 1 to 3 weeks.

• The incubation period for yersiniosis is 1 to 10 days • Tonsillitis and mesenteric adenitis may be present. • Postinfection sequelae may include erythema nodosum,

erythema multiforme, and reactive polyarthritis.


Rotavirus • Watery diarrhea

• Begins abruptly with nausea, vomiting, fever and headache.

• Incubation period of 1-4 days. May persist for 4 to 5 days.

• Primary mode of transmission is fecal-oral. • Most pediatric infections due to Group A rotavirus strains.

Groups B and C are also known to be pathogenic. • Viruses survive on dry fomites for up to 60 days. • Good hand-washing technique is critical when caring for

patients with rotavirus gastroenteritis.


Norovirus

• Watery diarrhea.

• Nausea, vomiting, abdominal cramps. Low-grade fever and myalgias. Dehydration may occur in severe cases.

• Incubation of 24-36 hours. Resolution within 24-48 hours.

• Transmission is thought to be primarily fecal oral. It appears that aerosolization may also lead to infection.

• Numerous outbreaks related to consumption of raw shellfish, particularly oysters, have also been reported.

• Viral shedding may be present for 2 or more weeks.


Entamoeba histolytica

• Mild diarrhea followed by dysentery.

• Low-grade fever, abdominal cramping, and anemia. Severe pancolitis mimicking inflammatory bowel disease. Amebic liver abscess formation is a well-known entity.

• Illness 2 to 4 weeks after exposure. • Common in tropics where poverty is prevalent. North

America, most frequently seen among institutionalized persons, MSM, and immigrants or travelers.

• Contaminated food or water.


Entamoeba histolytica Life Cycle


Giardia lamblia

• Diarrhea with steatorrhea

• Abdominal pain and cramping, flatulence, nausea and vomiting.

• Ill 2 to 4 weeks after ingestion.

• Contaminated food or water, or direct fecal-oral contact. • Daycare centers, international travelers, and MSM. • Post-infection irritable bowel symptoms have been

reported in significant number of patients.


Giardiasis Life Cycle


Cryptosporidium • Watery diarrhea

• Infection may be asymptomatic but often

leads to abdominal cramping, malaise. Systemic manifestations occasionally occur.

• C parvum and C hominis cause disease. • Particularly problematic among HIV-infected individuals. • Waterborne illness, may also be traced to contaminated

food or person-to-person contact. • To prevent transmission, persons who have been infected

with Cryptosporidium should not swim for at least 2 weeks after cessation of diarrhea.


Cryptosporidiosis


Cyclosporiasis

• Persistent diarrhea.

• Anorexia, nausea/vomiting, abdominal cramps, flatulence, low grade fever, weight loss. Chronic diarrhea in immunosuppressed.

• Contaminated food and water; no person-to-person.

• C. cayatanensis found only in humans.


Cyclosporiasis


Complications of Bacterial Diarrhea

Guillain-Barré syndrome

Campylobacter jejuni 40% cases of GBS caused by C. jejuni; molecular mimicry LOS

Reactive arthritis

Hemolytic-uremic syndrome (HUS)

Bacteremia

Dehydration

Complication

C. jejuni, Salmonella, S. flexneri

STEC, S. dysenteriae type 1

Salmonella spp., C. fetus

Any bacterial pathogen

Associated Agents

Occurs in 2.1 per 100 000 Campylobacter infections

Pathogenesis due to shiga toxin absorption and damage

Certain conditions predispose to systemic Salmonella infection

Most important complication of watery diarrhea

Clinical Considerations

Irritable bowel syndrome

Most bacterial pathogens

≤ 10% incidence following bacterial enteric infection


Diagnosis

• Risk factors • Geography, baseline health,

exposures

• Clinical picture • Inflammatory vs. non-inflammatory diarrhea

• Laboratory

• Assets may be non-existent • Some pathogens evade routine laboratory tests

• Diarrheagenic E. coli (ETEC, EAEC, EIEC) • Norovirus


Diagnosis: Stool Culture • Stool culture: clinical indications

• Severe diarrhea (≥ 6 loose/liquid stools/24 hrs) • Febrile enteritis and/or dysentery • Persistent diarrhea (≥ 14 days duration) • Bloody diarrhea (at risk for Shigella, STEC) • Inflammatory enteritis (by stool diagnostics)

• Stool parasitology: clinical indications

• Persistent diarrhea (≥ 14 days duration) • Diarrhea in traveler from known high risk region


Personal Prevention Measures • Food

– Eat • Food that is cooked and served hot

• Hard-cooked eggs

• Fruits and vegetables you have washed in clean water or peeled yourself

• Pasteurized dairy products


Personal Prevention Measures • Food

– Don't Eat • Food served at room temperature • Food from street vendors • Raw or soft-cooked (runny) eggs • Raw or undercooked (rare) meat or fish • Unwashed or unpeeled raw fruits and vegetables • Condiments (such as salsa) made with fresh ingredients

• Salads • Flavored ice or popsicles • Unpasteurized dairy products • ”Bushmeat” (monkeys, bats, or other wild game)


Personal Prevention Measures • Beverages

– Drink • Water, sodas, or sports drinks that are bottled and sealed (carbonated is safer)

• Water that has been disinfected (boiled, filtered, treated)

• Ice made with bottled or disinfected water

• Hot coffee or tea

• Pasteurized milk

http://wwwnc.cdc.gov/travel/page/water-disinfection.htm


Personal Prevention Measures • Beverages

– Don't Drink • Tap or well water

• Fountain drinks

• Ice made with tap or well water

• Drinks made with tap or well water (such as reconstituted juice)

• Unpasteurized milk


Personal Prevention Measures • Bathing and Swimming

– Unclean water can also make you sick if you swallow or inhale it while bathing, showering, or swimming. Try not to get any water in your nose or mouth.

– In some areas, tap water may not even be safe for brushing your teeth, and you should use bottled water.

– People who are elderly or have weakened immune systems might want to stay away from areas where there is a lot of steam and water vapor that can be inhaled, such as showers and hot tubs.


Treatment: Volume Replacement

• Cornerstone of diarrhea treatment • Military settings, insensible fluid losses increased with

high ambient temperature, intense physical activity • Oral rehydration

– Physiological principle: Integrity of coupled transport of Na+ (plus H2O and other electrolytes) with glucose or amino acids

– Effective in majority of patients • Intravenous rehydration

– Severe dehydration – Altered sensorium – Intractable vomiting


Treatment: Symptomatic

• Loperamide (imodium): antimotility agent of choice – Slows down peristalsis, intestinal transit – Increased fluid and salt absorption – 4 mg po, 2 mg prn liquid stool (up to 16 mg per day) – Okay to use for non-bloody, non-febrile diarrhea.

• Bismuth subsalicylate (Pepto Bismol) – Reduces number of stools – Does not limit duration of disease – 525 mg (2 tabs) every 30 min for 8 doses – Contraindicated in persons on salicylates, warfarin – Can interfere with doxycycline absorption – Stools will be black


Treatment: Antibiotics

• Indicated for moderate to severe diarrhea/dysentery • Combination of antibiotic PLUS loperamide leads to rapid

resolution of illness • Re-evaluate patient if no improvement after 1 wk

Antibiotic (po) Dosage (adult) Considerations

Fluoroquinolones

Norfloxacin 800 mg once or 400 mg bid Re-evaluate 12-24 h after single dose. Continue for up to 3 d if diarrhea not resolved

Ciprofloxacin 750 mg once or 500 mg bid

Ofloxacin 400 mg once or 200 mg bid

Levofloxacin 500 mg once or 500 qd

Azithromycin 1000 mg once or 500 mg bid x 3d Use when C. jejuni suspected

Rifaximin 200 mg tid Effective for non-invasive E coli


Increasing Fluoroquinolone Resistance among Campylobacter in Travelers

Vlieghe ER et al, J Travel Med 2008;15:419-25

Region

1994-2000 2001-2006

No. isolates No. resistant isolates

Resistance rate (%) No. isolates

No. resistant isolates

Resistance rate (%)

Africa

Asia

Caribbean, Central & So. America

162

208

36

22

74

10

13.6

35.6

27.8

114

95

33

36

67

20

31.6

70.5

60.6

Study site: Travel clinic, Antwerp, Belgium Erythromycin resistance showed modest increase over same

period to 8.6% resistance in 2006 Use Azithromycin in SE ASIA, 1000 mg x 1 = enough


Antibiotics + Loperamide Antibiotics alone or plus loperamide (outcome: cure at 24 hours) Riddle MS et al, CID 2008

Placebo vs antibiotics alone (outcome: cure at 72 hours) Bruyn G et al Cochrane Collab 2004

TLUS = 24 – 36 hours

DuPont,1982

Ericsson, 1983

Mattila, 1993

Salam, 1994

Steffen, 1993

Wistrom, 1989

Total

Favors Placebo Favors Antibiotics

13.96 [5.47,35.65]

10.52 [3.43,32.28]

3.34 [149,7.48]

5.73 [1.14,28.92]

4.63 [2.20,9.75]

4.72 [1.96,11.39]

5.90 [4.06,8.57]

TLUS ~ 12 hours

Odds Ratio

Favors solo antibiotic therapy Favors combination therapy

1.0

Study Regimen Odds ratio (95% CI)

2.74 (1.07, 7.03)

CIP 500mg, b.i.d 2.28 (0.91, 5.70)

CIP 750mg, single dose [8] 1.01 (0.44, 2.31)

5.88 (2.02, 17.10)

RIF 200mg, t.i.d 2.78 (1.48, 5.20)

AZTH 500mg, single dose [4] 3.64 (1.49, 8.86)

Overall 2.58 (1.84, 3.61)

5.0 10.0 Odds Ratio

Favors solo antibiotic therapy Favors combination therapy

1.0

Study Regimen [1, 2] Odds ratio (95% CI)

TMP-SMX 800/160mg, b.i.d x 3d [7]

CIP 500mg, x 3d [3]

CIP 750mg, single dose

OFL 400mg, single dose[6] 5.88 (2.02, 17.10)

RIF 200mg, t.i.d . x 3d [5]

AZTH 500mg, single dose

Overall

5.0 10.0


Rifaximin and Chemoprophylaxis of Travelers’ Diarrhea

• Poorly adsorbed po antibiotic – Absent side effects

• Low levels of resistance among enteric pathogens

• Prophylaxis against travelers’ diarrhea for short-term travelers

– ETEC predominant regions – ≥70% protection conferred

• Limited studies to date – Geographically limited – Predominance of

ETEC/EAEC – Short duration travel

• Impact of widespread

usage for prophylaxis unknown

diarrhea - walter reed army institute of research trop. med...• watery diarrhea • low-grade...

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